Indanes as PD-L1 inhibitors

ABSTRACT

Compounds represented by Formula (I) or (II):are provided herein, or a pharmaceutically acceptable salt, or a prodrug or bioisostere thereof; wherein R1, R2a, R2b, R2c, R3, R4, R5, R6a, R6b, R2a′, R2b′, R2c′, R3′, R4′, R5′, R6a′, R6b′, Y, Y′, and the subscripts m and n are as defined herein.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is an application claiming benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62/872,541 filed Jul. 10,2019, which is incorporated herein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE INVENTION

Programmed cell death protein-1 (PD-1) is a member of the CD28superfamily that delivers negative signals upon interaction with its twoligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed andexert a wide range of immunoregulatory roles in T cell activation andtolerance. PD-1 and its ligands are involved in attenuating infectiousimmunity and tumor immunity, and facilitating chronic infection andtumor progression.

Modulation of the PD-1 pathway has therapeutic potential in varioushuman diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011);350:17-37). Blockade of the PD-1 pathway has become an attractive targetin cancer therapy. Therapeutic antibodies that block the programmed celldeath protein-1 (PD-1) immune checkpoint pathway prevent T-cell downregulation and promote immune responses against cancer. Several PD-1pathway inhibitors have shown robust activity in various phases ofclinical trials (R D Harvey, Clinical Pharmacology and Therapeutics(2014); 96(2), 214-223).

Agents that block the interaction of PD-L1 with either PD-1 or CD80 aredesired. Some antibodies have been developed and commercialized. A fewpatent applications disclosing non-peptidic small molecules have beenpublished (WO 2015/160641, WO 2015/034820, and WO 2017/066227 andWO2018/009505 from Bristol-Myers Squibb; WO 2015/033299 and WO2015/033301 from Aurigene; WO 2017/070089, US 2017/0145025, WO2017/106634, US2017/0174679, WO2017/192961, WO2017/222976,WO2017/205464, WO2017/112730, WO2017/041899 and WO2018/013789 fromIncyte, WO2018/006795 from Maxinovel and WO2018/005374 fromChemoCentryx). However there is still a need for alternative compoundssuch as small molecules as inhibitors of PD-L1, and which may haveadvantageous characteristics in term of oral administration, stability,bioavailability, therapeutic index, and toxicity.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds having Formula (I) or (II):

-   -   or a pharmaceutically acceptable salt, or a prodrug or        bioisostere thereof; wherein R¹, R^(2a), R^(2b), R^(2c), R³, R⁴,        R⁵, R^(6a), R^(6b), R^(2a′), R^(2b′), R^(2c′), R^(3′), R^(4′),        R^(5′), R^(6a′), R^(6b′), Y, Y′, and the subscripts m and n are        as defined herein.

In addition to the compounds provided herein, the present disclosurefurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods associated with preparation and useof such compounds. In some embodiments, the compounds are used intherapeutic methods to treat diseases associated with the PD-1/PD-L1pathway.

BRIEF DESCRIPTION OF THE DRAWINGS

None

DETAILED DESCRIPTION OF THE INVENTION Abbreviation and Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error for the quantity measured given the nature or precisionof the measurements. Typical, exemplary degrees of error are within 20percent (%), preferably within 10%, and more preferably within 5% of agiven value or range of values. Alternatively, and particularly inbiological systems, the terms “about” and “approximately” may meanvalues that are within an order of magnitude, preferably within 5-foldand more preferably within 2-fold of a given value. Numerical quantitiesgiven herein are approximate unless stated otherwise, meaning that theterm “about” or “approximately” can be inferred when not expresslystated.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon group,having the number of carbon atoms designated (i.e. C₁₋₈ means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl and3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers.

The term “cycloalkyl” refers to a hydrocarbon ring or rings having theindicated number of ring atoms (e.g., C₃₋₆ cycloalkyl) and being fullysaturated or having no more than one double bond between ring vertices.“Cycloalkyl” is also meant to refer to bicyclic and polycyclichydrocarbon rings such as, for example, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, etc. The bicyclic or polycyclic rings may befused, bridged, spiro or a combination thereof.

The term “heterocycloalkyl” or “heterocyclyl” refers to a cycloalkylgroup that contain from one to five heteroatoms selected from N, O, andS, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. The heterocycloalkylmay be a monocyclic, a bicyclic or a polycylic ring system. The bicyclicor polycyclic rings may be fused, bridged, spiro or a combinationthereof. It is understood that the recitation ‘C₄₋₁₂ heterocyclyl’, forexample, refers to a group having from 4 to 12 ring members where atleast one of the ring members is a heteroatom. Non limiting examples ofheterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone,hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent group derived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—.An alkylene group can be linear or branched. An examples of the latterare —CH₂C(CH₃)₂CH₂—, —CH₂C(CH₃)₂— or —CH(CH₃)CH₂CH₂—. Typically, analkyl (or alkylene) group will have from 1 to 12 carbon atoms, withthose groups having 8 or fewer carbon atoms being preferred in thepresent disclosure. Similarly, “alkenylene” and “alkynylene” refer tothe unsaturated forms of “alkylene” having double or triple bonds,respectively.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “hydroxyalkyl” or “alkyl-OH” refers to an alkyl group, asdefined above, where at least one (and up to three) of the hydrogenatoms is replaced with a hydroxy group. As for the alkyl group,hydroxyalkyl groups can have any suitable number of carbon atoms, suchas C₁₋₆. Exemplary hydroxyalkyl groups include, but are not limited to,hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1- or2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or3-position), and 2,3-dihydroxypropyl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently.

The term “heteroaryl” refers to a five- to ten-membered aromatic ring(or rings) that have from one to five heteroatom ring vertices, each ofwhich is selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. It is understood that the recitation‘C₅₋₁₀ heteroaryl’, refers to a heteroaryl moiety having from 5 to 10ring members where at least one of the ring members is a heteroatom.Non-limiting examples of aryl groups include phenyl, naphthyl andbiphenyl, while non-limiting examples of heteroaryl groups includepyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl,purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl and the like. Substituents for each of theabove noted aryl and heteroaryl ring systems are selected from the groupof acceptable substituents described below.

When any of the above terms (e.g., “alkyl,” “aryl” and “heteroaryl”) arereferred to as ‘substituted’ without further notation on thesubstituents, the substituted forms of the indicated group will be asprovided below.

Substituents for the alkyl groups (including those groups often referredto as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety ofgroups selected from: -halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-,6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used by itself oras part of another group refers to an alkyl group wherein twosubstitutents on the carbon that is closest to the point of attachmentfor the group is replaced with the substitutent ═O (e.g., —C(O)CH₃,—C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)R′, —S(O)₂NR′, —S(O)₂NR′R″, —NR′S(O)₂R″,—N₃, perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, andunsubstituted aryloxy-C₁₋₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)-B-, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The disclosure herein further relates to prodrugs and bioisosteresthereof. Suitable bioisosteres, for example, will include carboxylatereplacements (phosphonic acids, phosphinic acids, sulfonic acids,sulfinic acids, and acidic heterocyclic groups such as tetrazoles).Suitable prodrugs will include those conventional groups known tohydrolyze and/or oxidize under physiological conditions to provide acompound of Formula I.

The terms “patient” and “subject” include primates (especially humans),domesticated companion animals (such as dogs, cats, horses, and thelike) and livestock (such as cattle, pigs, sheep, and the like).

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer to the compound in which one of the isomers is present andsubstantially free of the other isomer. ‘Substantially free of’ anotherisomer indicates at least an 80/20 ratio of the two isomers, morepreferably 90/10, or 95/5 or more. In some embodiments, one of theisomers will be present in an amount of at least 99%.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.For example, the compounds may be prepared such that any number ofhydrogen atoms are replaced with a deuterium (²H) isotope. The compoundsof the present disclosure may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. Unnatural proportions of an isotope may be defined as rangingfrom the amount found in nature to an amount consisting of 100% of theatom in question. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere within this application. Forinstance, isotopic variants of the compounds of the disclosure may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the disclosure canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

COMPOUNDS

In one aspect, the present disclosure provides compounds having Formula(I) or Formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, or hydrate        thereof, wherein    -   Y and Y′ are each independently selected from the group        consisting of O, NH and N(C₁₋₄ alkyl);    -   R¹ is independently selected from the group consisting of H,        halogen, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl and        —O—C₁₋₄ haloalkyl;    -   each R^(2a), R^(2b), R^(2c), R^(2a′), R^(2b′) and R^(2c′) is        independently selected from the group consisting of H, halogen,        —CN, —R^(a), —CO₂R^(b), —CONR^(b)R^(c), —OC(O)NR^(b)R^(c),        —NR^(c)C(O)R^(b), —NR^(c)C(O)₂R^(a), —NR^(b)—C(O)_(NR)        ^(b)R^(c), —NR^(b)R^(c), —OR^(b), —X¹—OR^(b), —X¹—OR^(b),        —X¹—NR^(b)R^(c), —X¹—CO₂R^(b), —SF₅, and —S(O)₂NR^(b)R^(c),        wherein each X¹ is a C₁₋₄ alkylene; each R^(b) and R^(c) is        independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈        haloalkyl, or when attached to the same nitrogen atom can be        combined with the nitrogen atom to form a five or six-membered        ring having from 0 to 2 additional heteroatoms as ring members        selected from N, O and S, and optionally substituted with oxo;        each R^(a) is independently selected from the group consisting        of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl;    -   R³ and R^(3′) are each independently selected from the group        consisting of —NR^(d)R^(e) and 4- to 12-membered monocyclic,        bicyclic or spirocyclic non-aromatic heterocyclic ring,        optionally substituted with 1 to 6 R^(3a); wherein        -   R^(d) is selected from the group consisting of H, C₁₋₈            haloalkyl and C₁₋₈ alkyl;        -   R^(e) is selected from H, —C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈            hydroxyalkyl, —X²—CO₂R^(g), —X²—CONR^(g)R^(h), and            —X²—CONHSO₂R^(g), —X²—SO₂NR^(g)R^(h), —X²—SO₃R^(g),            —X²—B(OH)₂, —X²—PO₃H₂, —X²—C(O)NHOH, —X²—NR^(g)R^(h),            —C(O)R^(g), C₃₋₁₀ cycloalkyl, —C₃₋₁₀ cycloalkyl-COOR^(g),            —C₃₋₁₀ cycloalkyl-OR^(g), C₄₋₈ heterocyclyl, —C₄₋₈            heterocyclyl, —C₄₋₈—COOR^(g), —C₄₋₈ heterocyclyl-OR^(g),            —X²—C₄₋₈ heterocyclyl, —C(═O)O—X²—C₄₋₈ heterocyclyl,            —X²C₃₋₁₀ cycloalkyl, C₅₋₁₀ heteroaryl, —X²—C₅₋₁₀ heteroaryl,            —X²—C₆₋₁₀ aryl, —X²—(C═O)—C₆₋₁₀ aryl, —CO₂—X²—O₂C—C₁₋₈            alkyl, —X²—NH(C═O)—₂₋₈ alkenyl, —X²—NH(C═O)—C₁₋₈ alkyl,            —X²—NH(C═O)—C₂₋₈ alkenyl, —X²—(C═O)—NH—X²—COOR^(g), and            —X²—(C═O)—NH—X²—OR^(g) optionally substituted with CO₂H;            wherein the alkyl or alkylene portions of R^(c) are            optionally further substituted with from 1 to 3 substituents            independently selected from OH, COOH, SO₂NH₂, CONH₂,            C(O)NHOH, COO—C₁₋₈ alkyl, and PO₃H₂; the C₅₋₁₀ heteroaryl            and the C₆₋₁₀ aryl portions of R^(e) are optionally            substituted with 1 to 3 substituents independently selected            from OH, B(OH)₂, COOH, NH₂, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,            COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkylene-OH,            C₁₋₄alkylene-SO₂NH₂, C₁₋₄alkylene CONH₂, C₁₋₄            allkylene-C(O)NHOH, C₁₋₄alkylene-PO₃H₂, and            C₁₋₄alkylene-COOH; and the C₄₋₈ heterocyclyl and            C₃₋₁₀cycloalkyl portions of R^(e) are optionally substituted            with 1 to 4 R^(w) substituents;    -   or        -   R^(e) combined with the N to which it is attached is a            mono-amino acid, di- or tri-peptide comprising natural amino            acids and non-natural amino acids, wherein the non-natural            amino acids have an alpha carbon substituent selected from            the group consisting of C₂₋₄ hydroxyalkyl, C₁₋₃            alkyl-guanidinyl, and C₁₋₄ alkyl-heteroaryl, and wherein the            alpha carbon of each natural or non-natural amino acid is            optionally further substituted with a methyl group, and the            terminal moiety of the mono-, di-, or tri-peptide is            selected from the group consisting of C(O)OH, C(O)O—C₁₋₆            alkyl, C(O)NH₂ and PO₃H₂;        -   each R^(3a) is independently selected from the group            consisting of halogen, —CN, oxo, —R^(f), —CO₂R^(g),            —CONR^(g)R^(h), —CONHC₁₋₆ alkyl-OH, —C(O)R^(g), —OC(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(g)C(O)R^(h), —NR^(g)C(O)₂R^(h),            —CONHOH, —PO₃H₂, —NR^(g)—X²—C(O)₂R^(h),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —O—X²—OR^(g), —O—X²—NR^(g)R^(h),            —O—X²—CO₂R^(g), —O—X²—CONR^(g)R^(h), —X²—OR^(g),            —X²—NR^(g)R^(h), —X²—CO₂R^(g), —X²—CONR^(g)R^(h),            —X²—CONHSO₂R^(g) and SF₅; wherein X² is C₁₋₆ alkylene and is            optionally further substituted with OH, NH₂, SO₂NH₂, CONH₂,            C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl or CO₂H, wherein each R^(g)            and R^(h) is independently selected from hydrogen, C₁₋₈            alkyl optionally substituted with 1 to 2 substituents            selected from OH, NH₂, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,            COO—C₁₋₈alkyl and CO₂H, and C₁₋₈ haloalkyl optionally            substituted with 1 to 2 substituents selected from OH, NH₂,            SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl and CO₂H, or            when attached to the same nitrogen atom R^(g) and R^(h) can            be combined with the nitrogen atom to form a five or            six-membered ring having from 0 to 2 additional heteroatoms            as ring members selected from N, O or S, and optionally            substituted with oxo; each R^(f) is independently selected            from the group consisting of —OH, C₁₋₈ alkyl, C₂₋₈ alkenyl,            and C₁₋₈ haloalkyl each of which may be optionally            substituted with OH, NH₂, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,            COO—C₁₋₈alkyl or CO₂H;        -   each R^(w) substituent is independently selected from C₁₋₄            alkyl, C₁₋₄ alkylene-OH, C₁₋₄ alkylene-COOH, C₁₋₄            alkylene-SO₂NH₂, C₁₋₄ alkylene-CONH₂, C₁₋₄            alkylene-C(O)NHOH, C₁₋₄ alkylene-PO₃H, OH, COO—C₁₋₈ alkyl,            COOH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂ and oxo;    -   R⁴ and R^(4′) are each independently selected from the group        consisting of O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, C₆₋₁₀ aryl, C₅₋₁₀        heteroaryl, —O—C₁₋₄ alkyl-C₄₋₇ heterocycloalkyl, —O—C₁₋₄        alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, each of        which is optionally substituted with 1 to 5 R^(4a);        -   each R^(4a) is independently selected from the group            consisting of halogen, —CN, —R^(i), —CO₂R^(j),            —CONR^(j)R^(k), —C(O)R^(j), —OC(O)NR^(j)R^(k),            —NR^(j)C(O)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(i),            —NR^(j)—C(O)NR^(j)R^(k), —NR^(j)R^(k), and —OR^(j); wherein        -   each R^(i) is independently selected from the group            consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl;            and optionally when two R^(4a) substituents are on adjacent            atoms, they are combined to form a fused five or            six-membered carbocyclic or heterocyclic ring optionally            substituted with oxo;        -   each and R^(j) and R^(k) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S, and optionally substituted with oxo;    -   each n is independently 0, 1, 2 or 3;    -   each R^(r) and R^(5′) is independently selected from the group        consisting of halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s),        —C(O)R^(r), —NR^(r)R^(s), and —OR^(r), wherein        -   each R^(r) and R^(s) is independently selected from            hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S, and optionally substituted with oxo; each R^(q) is            independently selected from the group consisting of C₁₋₈            alkyl, and C₁₋₈ haloalkyl;    -   R^(6a) and R^(6a′) are each independently selected from the        group consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl;    -   each m is independently 0, 1, 2, 3 or 4;    -   each R^(6b) and R^(6b′) is independently selected from the group        consisting of F, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In one group of embodiments, the compounds provided herein arerepresented by Formula (I).

In one group of embodiments, the compounds provided herein arerepresented by Formula (II).

In one group of embodiments, the compounds of Formula (I) or (II) arethose wherein Y and Y′ are each independently selected from the groupconsisting of O and NH.

In one group of embodiments, the compounds of Formula (I) or (II) arethose wherein Y and Y′ are each O.

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each subscript n is 0 or 1. In some embodiments, the compoundsof Formula (I) or (II) are those wherein each subscript m is 0 or 1. Insome embodiments, the compounds of Formula (I) or (II) are those whereineach subscript n is 0 or 1, and each subscript m is 0 or 1.

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R³ and R^(3′) is a 4- to 9-membered monocyclic orspirocyclic non-aromatic heterocyclic ring, optionally substituted with1 to 4 R^(3a).

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R³ and R^(3′) is independently —NR^(d)R^(e).

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R³ and R^(3′) is independently —NR^(d)R^(e) and R^(e)combined with the N to which it is attached is a natural or non-naturalamino acid, wherein the non-natural amino acids have an alpha carbonsubstituent selected from the group consisting of C₂₋₄ hydroxyalkyl andC₁₋₃ alkyl-guanidinyl, and wherein the alpha carbon of each natural ornon-natural amino acid is optionally further substituted with a methylgroup, and the terminal moiety is selected from the group consisting ofC(O)OH, C(O)O—C₁₋₆ alkyl, and C(O)NH₂.

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R³ and R^(3′) is independently —NR^(d)R^(e) and R^(e)combined with the N to which it is attached is a natural or non-naturalamino acid, wherein the non-natural amino acids have a C₂₋₄ hydroxyalkylalpha carbon wherein the alpha carbon of each natural or non-naturalamino acid is further substituted with a methyl group, and the terminalmoiety is selected from the group consisting of C(O)OH, C(O)O—C₁₋₄alkyl, and C(O)NH₂.

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R^(2a), R^(2b), R^(2c), R^(2a′), R^(2b′) and R^(2c′) isindependently selected from the group consisting of H, halogen, —CN,—R^(a), —CO₂R^(b), —CONR^(b)R^(c), —NR^(b)R^(c), and —OR^(b), whereineach R^(b) and R^(c) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogen atomcan be combined with the nitrogen atom to form a five or six-memberedring having from 0 to 2 additional heteroatoms as ring members selectedfrom N, O and S, and optionally substituted with oxo; each R^(a) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl.

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R⁴ and R^(4′) is independently selected from the groupconsisting of O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, —O—C₁₋₄ alkyl-C₆₋₁₀aryland —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, each of which is optionallysubstituted with 1 to 5 R^(4a).

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R⁴ and R^(4′) is independently selected from the groupconsisting of O—C₁₋₈ alkyl, —O—C₁₋₄ alkyl-phenyl and —O—C₁₋₄alkyl-pyridyl, each of which is optionally substituted with 1 to 3R^(4a).

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R^(2a), R^(2b), R^(2c), R^(2a′), R^(2b′) and R^(2c′) isindependently selected from the group consisting of H, halogen, —CN,—R^(a), —CO₂R^(b), —CONR^(b)R^(c), —NR^(b)R^(c), and —OR^(b); whereineach R^(b) and R^(c) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogen atomcan be combined with the nitrogen atom to form a five or six-memberedring having from 0 to 2 additional heteroatoms as ring members selectedfrom N, O and S, and optionally substituted with oxo; each R^(a) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; each R³ is a 4- to 9-membered monocyclic orspirocyclic non-aromatic heterocyclic ring, optionally substituted with1 to 4 R^(3a); and each R⁴ is selected from the group consisting ofO—C₁₋₈ alkyl, —O—C₁₋₄ alkyl-phenyl and —O—C₁₋₄ alkyl-pyridyl, each ofwhich is optionally substituted with 1 to 3 R^(4a).

In some embodiments, the compounds of Formula (I) or (II) are thosewherein each R^(2a), R^(2b), R^(2c), R^(2a′), R^(2b′) and R^(2c′) isindependently selected from the group consisting of H, halogen, —CN,—R^(a), —CO₂R^(b), —CONR^(b)R^(c), —NR^(b)R^(c), and —OR^(b); whereineach R^(b) and R^(c) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogen atomcan be combined with the nitrogen atom to form a five or six-memberedring having from 0 to 2 additional heteroatoms as ring members selectedfrom N, O and S, and optionally substituted with oxo; each R^(a) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; each R³ is —NR^(d)R^(e) and R^(e) combinedwith the N to which it is attached is a natural or non-natural aminoacid, wherein the non-natural amino acids have an alpha carbonsubstituent selected from the group consisting of C₂₋₄ hydroxyalkyl andC₁₋₃ alkyl-guanidinyl, and wherein the alpha carbon of each natural ornon-natural amino acid is optionally further substituted with a methylgroup, and the terminal moiety is selected from the group consisting ofC(O)OH, C(O)O—C₁₋₆ alkyl, and C(O)NH₂; and each R⁴ is selected from thegroup consisting of O—C₁₋₈ alkyl, —O—C₁₋₄ alkyl-phenyl and —O—C₁₋₄alkyl-pyridyl, each of which is optionally substituted with 1 to 3R^(4a).

In some embodiments, the compounds of Formula (II) are those wherein R¹is H, halogen, CN or C₁₋₄ alkyl.

In some selected embodiments, including any of the above notedembodiments, further embodiments include the compounds of Formula (I) or(II) wherein each R³ and R^(3′) is independently selected from the groupconsisting of

In some embodiments, for each of Formula (I) and (II), and the furtherselected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those selected from Table 1, having ++ or+++ activity.

In addition to the compounds provided above, pharmaceutically acceptablesalts of those compounds are also provided. In some embodiments, thepharmaceutically acceptable salts are selected from ammonium, calcium,magnesium, potassium, sodium, zinc, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, hydrochloric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, acetic, propionic,isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, arginate, glucuronic acid and galactunoric acids. Insome embodiments, the pharmaceutically acceptable salts are selectedfrom ammonium, calcium, magnesium, potassium, sodium, hydrochloric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, acetic, propionic, isobutyric, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, arginate, glucuronicacid and galactunoric acids. In some embodiments, the pharmaceuticallyacceptable salts are sodium or hydrochloric.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

An ester may be used as a prodrug for the corresponding carboxylic acid.A C₁₋₁₀ alkyl ester or a C₁₋₁₀ haloalkyl ester may be used as a prodrugfor the corresponding carboxylic acid. The following esters may be used:tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

PHARMACEUTICAL COMPOSITIONS

In addition to the compounds provided herein, compositions of thosecompounds will typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In another embodiment, a pharmaceutical composition comprising acompound of the present disclosure including a compound of Formulae (I)or (II), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, is provided.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. In some embodiments, the oneor more additional therapeutic agent is selected from the groupconsisting of an antimicrobial agent, an antiviral agent, a cytotoxicagent, a gene expression modulatory agent, a chemotherapeutic agent, ananti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent,an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, aradiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. In some embodiments, the one or moreadditional therapeutic agent is an antagonist of a chemokine and/orchemoattractant receptor, which includes but is not limited to, CCR1,CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12,CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and/or C5aR.Chemokine and/or chemoattractant receptor antagonists are known in theart and described in, for example, WO2007/002667, WO2007/002293,WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804,WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815,WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561,WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490,WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393,WO2017/127409, WO2017/087607, WO2017/087610, WO2017/176620,WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644,WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374,WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916,WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/orchemoattractant receptor antagonists also include CCX354, CCX9588,CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650,CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled with a carrier thatis a suitable polymer for targetable drug carriers. Such polymers caninclude polyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

METHODS OF TREATING DISEASES AND DISORDERS

The compounds of the disclosure may be used as immunomodulators. Thecompounds of the disclosure may be used as agonists, antagonists,partial agonists, inverse agonists, inhibitors of PD-1 and/or PD-L1 in avariety of contexts, both in vitro and in vivo. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the PD-1/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used as inhibitors of PD-L1. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the CD80/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used to inhibit the interaction between PD-1 and PD-L1and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In someembodiments, the compounds of the disclosure may be used to inhibitVISTA and/or TIM-3. In some embodiments, the compounds of the disclosuremay be inhibitors of the PD-1/PD-L1 protein protein interaction andinhibitors of VISTA and/or TIM-3. In some embodiments, in addition tobeing inhibitors of the PD-1/PD-L1 protein protein interaction, thecompounds of the disclosure may be inhibitors of CTLA-4 and/or BTLAand/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/orCD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80.

The compounds of the disclosure may be contacted with the receptor theyinteract with, in aqueous solution and under conditions otherwisesuitable for binding of the ligand to the receptor. The receptor may bepresent in suspension (e.g., in an isolated membrane or cellpreparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the disclosure contacted withthe receptor should be sufficient to inhibit the PD-1/PD-L1 binding invitro as measured, for example, using an ELISA. The receptor may bepresent in solution or suspension, in a cultured or isolated cellpreparation or within a patient.

In some embodiments, the compounds of the present disclosure are usefulfor restoring and augmenting T cell activation. In some embodiments, thecompounds of the present disclosure are useful for enhancing an immuneresponse in a patient. In some embodiments, the compounds of the presentdisclosure are useful for treating, preventing, or slowing theprogression of diseases or disorders in a variety of therapeutic areas,such as cancer and infectious diseases.

In some embodiments, the compounds of the present disclosure can be usedfor treating patients suffering from conditions that are responsive toPD-1/PD-L1 protein protein interaction modulation.

In some embodiments, a method of modulating an immune response mediatedby the PD-1 signaling pathway in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of thepresent disclosure including a compound of Formulae (I) or (II), or apharmaceutically acceptable salt thereof or a composition comprising acompound of Formulae (I) or (II), or a pharmaceutically acceptable saltthereof, is provided.

In some embodiments, a method of enhancing, stimulating, modulatingand/or increasing the immune response in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormulae (I) or (II), or a pharmaceutically acceptable salt thereof or acomposition of a compound of the present disclosure including a compoundof Formulae (I) or (II), or a pharmaceutically acceptable salt thereof,is provided.

In some embodiments, a method of inhibiting growth, proliferation, ormetastasis of cancer cells in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure including a compound of Formulae (I)or (II), or a pharmaceutically acceptable salt thereof or a compositionof a compound of the present disclosure including a compound of Formulae(I) or (II), or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of treating a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormulae (I) or (II), or a pharmaceutically acceptable salt thereof or acomposition of a compound of the present disclosure including a compoundof Formulae (I) or (II), or a pharmaceutically acceptable salt thereof,is provided.

In some embodiments, the subject suffers from a disease or disorderselected from the group consisting of an infectious disease, a bacterialinfectious disease, a viral infectious disease a fungal infectiousdisease, a solid tumor, a hematological malignancy, an immune disorder,an inflammatory disease, and cancer. In some embodiments, the disease ordisorder is selected from the group consisting of melanoma,glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma,lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma,diffuse large B-cell lymphoma, primary mediastinal large B-celllymphoma, prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.

In some embodiments, a therapeutically effective amount of one or moreadditional therapeutic agents is further administered to the subject. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of an antimicrobial agent, anantiviral agent, a cytotoxic agent, a gene expression modulatory agent,a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an immunotherapeutic agent, an anti-hormonal agent, ananti-fibrotic agent, radiotherapy, a radiotherapeutic agent, ananti-neoplastic agent, and an anti-proliferation agent. In someembodiments, the one or more additional therapeutic agent is anantagonist of a chemokine and/or chemoattractant receptor, whichincludes but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6,CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4,CXCR5, CXCR6, CXCR7, C3aR, and/or C5aR. Chemokine and/or chemoattractantreceptor antagonists are known in the art and described in, for example,WO2007/002667, WO2007/002293, WO/2003/105853, WO/2007/022257,WO/2007/059108, WO/2007/044804, WO2007/115232, WO/2007/115231,WO/2008/147815, WO2010/030815, WO2010/075257, WO2011/163640,WO2010/054006, WO2010/051561, WO2011/035332, WO2013/082490,WO2013/082429, WO2014/085490, WO2014/100735, WO2014/089495,WO2015/084842, WO2016/187393, WO2017/127409, WO2017/087607,WO2017/087610, WO2017/176620, WO2018/222598, WO2018/222601,WO2013/130811, WO2006/076644, WO2008/008431, WO2009/038847,WO2008/008375, WO2008/008374, WO2008/010934, WO2009/009740,WO2005/112925, WO2005/112916, WO2005/113513, WO2004/085384,WO2004/046092. Chemokine and/or chemoattractant receptor antagonistsalso include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664,CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022and/or CCX3384.

In some embodiments, the compounds of the present disclosure may be usedto inhibit an infectious disease. The infectious disease includes but isnot limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, thepathogenic infection by the virus Hepatitis (A, B, and C), herpes virus(e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus, pathogenicinfection by the bacteria chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, E. coli, legionella,diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,plague, leptospirosis, and Lyme's disease bacteria, pathogenic infectionby the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.),Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), GenusMucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomycesdermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis andHistoplasma capsulatum, and pathogenic infection by the parasitesEntamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoebasp., Giardia lambia, ryptosporidium sp., Pneumocystis carinii,Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosomacruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylusbrasiliensis.

In some embodiments, the compounds of the present disclosure may be usedto inhibit HIV infection, delay AIDS progression, deplete HIV viralreservoir or decrease the severity of symptoms or HIV infection andAIDS.

The compounds of the present disclosure may be used for the treatment ofcancers and precancerous conditions in a subject.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of thedisclosure are preferably administered to a patient (e.g., a human)intravenously, orally or topically. The effective amount may be anamount sufficient to modulate the PD-1/PD-L1 interaction and/or anamount sufficient to reduce or alleviate the symptoms presented by thepatient. Preferably, the amount administered is sufficient to yield aplasma concentration of the compound (or its active metabolite, if thecompound is a pro-drug) high enough to sufficiently modulate thePD-1/PD-L1 interaction. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

COMBINATIONS

A concomitant medicine comprising the compounds of the presentdisclosure and other drug may be administered as a combinationpreparation in which both components are contained in a singleformulation, or administered as separate formulations. Theadministration by separate formulations includes simultaneousadministration and administration with some time intervals. In the caseof the administration with some time intervals, the compound of thepresent disclosure can be administered first, followed by another drugor another drug can be administered first, followed by the compound ofthe present disclosure. The administration method of the respectivedrugs may be the same or different.

The dosage of the other drug can be properly selected, based on a dosagethat has been clinically used. The compounding ratio of the compound ofthe present disclosure and the other drug can be properly selectedaccording to age and weight of a subject to be administered,administration method, administration time, disorder to be treated,symptom and combination thereof. For example, the other drug may be usedin an amount of 0.01 to 100 parts by mass, based on 1 part by mass ofthe compound of the present disclosure. The other drug may be acombination of two or more kind of arbitrary drugs in a properproportion.

The compounds described herein may be used or combined with one or moretherapeutic agent such as an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. These therapeutic agents may be in the formsof compounds, antibodies, polypeptides, or polynucleotides.

The compounds described herein may be used or combined with one or moreof a therapeutic antibody, a bispecific antibody and “antibody-like”therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus,an oncolytic virus, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), aCAR (chimeric antigen receptor) T-cell immunotherapeutic agent, or anycombination thereof.

Examples of chemotherapeutics include an alkylation agent, nitrosoureaagent, antimetabolite, anticancer antibiotics, vegetable-originalkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist,aromatase inhibitor, P-glycoprotein inhibitor, platinum complexderivative, other immunotherapeutic drugs and other anticancer drugs.

The compounds described herein may be used or combined with a cancertreatment adjunct, such as a leucopenia (neutropenia) treatment drug,thrombocytopenia treatment drug, antiemetic and cancer pain interventiondrug, concomitantly or in a mixture form.

The compounds described herein may be used or combined with a kinaseinhibitor.

In one embodiment, the compounds of the present disclosure can be usedwith other immunomodulators and/or a potentiating agent concomitantly orin a mixture form. Examples of the immunomodulator include variouscytokines, vaccines and adjuvants. Examples of these cytokines, vaccinesand adjuvants that stimulates immune responses include but not limitedto GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3,IL-12, Poly (I:C) and CPG. The potentiating agents includecyclophosphamide and analogs of cyclophosphamide, anti-TGF and imatinib(Gleevac), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent)or other antiangiogenic agents, an aromatase inhibitor, such asletrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesisinhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists,and IL-18 antagonists.

In some embodiments, the compounds described herein may be used orcombined with one or more modulator of CCR1, CCR2, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, themodulator is an antagonist.

In some embodiments, the compounds described herein may be used orcombined with one or more chemokine and/or chemoattractant receptorantagonists described in, for example, WO2007/002667, WO2007/002293,WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804,WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815,WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561,WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490,WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393,WO2017/127409, WO2017/087607, WO2017/087610, WO2017/176620,WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644,WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374,WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916,WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/orchemoattractant receptor antagonists useful in the present disclosurealso include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664,CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022and/or CCX3384.

DOSAGE

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving the PD-1/PD-L1 interaction (about0.5 mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravenously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

In another aspect of the disclosure, the compounds of the disclosure canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. The compounds of the disclosure may also be used aspositive controls in assays for PD-1/PD-L1 interaction activity, i.e.,as standards for determining the ability of a candidate agent to bind toPD-1 and/or PD-L1, or as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

Also within the scope of the present disclosure are kits comprising acompound of the present disclosure or pharmaceutically acceptable saltsthereof and instructions for use. The kit can further contain at leastone additional reagent. Kits typically include a label indicating theintended use of the contents of the kit. The term label includes anywriting, or recorded material supplied on or with the kit, or whichotherwise accompanies the kit.

EXAMPLES

The following Examples illustrate various methods of making compounds ofthis disclosure including compounds of Formulae (I) or (II). Thefollowing examples are offered to illustrate, but not to limit theclaimed disclosure.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹H-NMR spectrawere recorded on a Varian Mercury 400 MHz NMR spectrometer. Significantpeaks are provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge. In the examples, a single m/z value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol or CH₃CN at 0.1 mg/mL and 1 microliter was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1000 Daltons. All compounds could be analyzed in the positive ornegative ESI mode, using acetonitrile/water with 1% formic acid as thedelivery solvent.

The following abbreviations are used in the Examples and throughout thedescription of the disclosure: TLC means Thin layer chromatography.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisdisclosure, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed unless a specific enantiomer is specified.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Synthesis of((2S,2′S)-2,2′-((((((1S,1′S)-2,2′,3,3′-tetrahydro-1H,1′H-[4,4′-biindene]-1,1′-diyl)bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoicAcid)

Step a: A solution of(S)-5-((4-chloro-2-formyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)methyl)nicotinonitrile(350 mg, 0.66 mmol),5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(320 mg, 0.66 mmol), and aqueous 2 M K₂CO₃ (1.0 mL, 2.0 mmol) in dioxane(13 mL) was degassed with nitrogen for 30 min before1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) complexedwith dichloromethane (110 mg, 0.13 mmol) was added. After degassing foran additional 10 min, the solution was heated to 90° C. and allowed tostir at this temperature for 4 h. Water (20 mL) was then added to thereaction mixture, and the mixture was extracted with 2:1 chloroform:isopropanol (20 mL×3). The combined organics were dried over MgSO₄,filtered, and concentrated in vacuo. Purification of the crude materialby flash chromatography (SiO₂, 50% EtOAc in hexane to 100% EtOAc) gave5,5′-((((((1S,1′S)-2,2′,3,3′-tetrahydro-1H,1′-[4,4′-biindene]-1,1′-diyl)bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile.

Step b: A solution of5,5′-((((((1S,1′S)-2,2′,3,3′-tetrahydro-1H,1′H-[4,4′-biindene]-1,1′-diyl)bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile(100 mg, 0.124 mmol) and L-serine (130 mg, 1.24 mmol) was stirred in DMF(4 mL) for 1 h before sodium triacetoxyborohydride (0.72 g, 3.4 mmol)was added in small portions over 10 min. The reaction mixture was leftto stir overnight at room temperature. The majority of DMF was removedin vacuo and the crude material was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% NH₄CO₃H) to obtain((2S,2′S)-2,2′-((((((1s,1′S)-2,2′,3,3′-tetrahydro-1H,1′H-[4,4′-biindene]-1,1′-diyl)bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoicacid). MS: (ES) m/z calculated for C₅₂H₄₆Cl₂N₆O₁₀ [M+H]⁺985.3, found985.7. ¹H NMR (400 MHz, Methanol-d₄) δ 9.02-8.99 (m, 2H), 8.91 (d, J=1.9Hz, 2H), 8.46 (t, J=1.9 Hz, 2H), 7.51 (s, 2H), 7.36-7.29 (m, 4H),7.30-7.24 (m, 2H), 7.08 (s, 2H), 6.08-5.94 (m, 2H), 5.41 (s, 4H), 4.61(s, 4H), 4.37 (d, J=13.1 Hz, 2H), 4.25 (d, J=13.0 Hz, 2H), 3.99 (dd,J=11.9, 3.9 Hz, 2H), 3.84 (dd, J=11.8, 7.1 Hz, 2H), 3.55 (dd, J=7.0, 3.9Hz, 2H), 3.09-2.93 (m, 2H), 2.83-2.69 (m, 2H), 2.60-2.44 (m, 2H),2.18-2.04 (m, 2H).

Biological Example: Enzyme-Linked Immunosorbent Assay—ELISA

96 Well plates were coated with 1 μg/mL of human PD-L1 (obtained fromR&D) in PBS overnight at 4° C. The wells were then blocked with 2% BSAin PBS (W/V) with 0.05% TWEEN-20 for 1 hour at 37° C. The plates werewashed 3 times with PBS/0.05% TWEEN-20 and the compounds were serialdiluted (1:5) in dilution medium and added to the ELISA plates. HumanPD-1 and biotin 0.3 μg/mL (ACRO Biosystems) were added and incubated for1 hour at 37° C. then washed 3 times with PBS/0.05% TWEEN-20. A secondblock was performed with 2% BSA in PBS (W/V)/0.05% TWEEN-20 for 10 minat 37° C. and the plates were washed 3 times with PBS/0.05% TWEEN-20.Streptavidin-HRP was added for 1 hour at 37° C. then the plates werewashed 3 times with PBS/0.05% TWEEN-20. TMB substrate was added andreacted for 20 min at 37° C. A stop solution (2 N aqueous H₂SO₄) wasadded. The absorbance was read at 450 nm using a micro-platespectrophotometer. The results are shown in Table 1: IC₅₀ values areprovided as follows: from 100 up to 10,000 nM (+); less than 100 nM(++).

TABLE 1 Compound ELISA ID Structure IC50 (nM) 1.001

+ 1.002

++ 1.003

+ 1.004

++ 1.005

+ 1.006

++ 1.007

1.008

++ 1.009

++ 1.010

+ 1.011

+ 1.012

++ 1.013

++ 1.014

++ 1.015

++ 1.016

+ 1.017

++ 1.018

++ 1.019

++ 1.020

++ 1.021

+ 1.022

+ 1.023

+ 1.024

++ 1.025

++ 1.026

++ 1.027

++ 1.028

++ 1.029

1.030

++ 1.031

++ 1.032

++ 1.033

++ 1.034

+ 1.035

++ 1.036

++ 1.037

++ 1.038

++ 1.039

++ 1.040

++ 1.041

+ 1.042

++ 1.043

+ 1.044

++ 1.045

++ 1.046

++ 1.047

++ 1.048

++ 1.049

++ 1.050

++ 1.051

++

The compounds of Table 1 were prepared using synthetic methods similarto those described in Example 1.

Particular embodiments of this invention are described herein forcarrying out the invention. Upon reading the foregoing, description,variations of the disclosed embodiments may become apparent toindividuals working in the art, and it is expected that those skilledartisans may employ such variations as appropriate. Accordingly, it isintended that the invention be practiced otherwise than as specificallydescribed herein, and that the invention includes all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the invention unless otherwise indicated herein orotherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and otherreferences cited in this specification are herein incorporated byreference as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.

What is claimed is:
 1. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis an optically pure or enriched isomer.
 3. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 4. A compound ofFormula (I),

or a pharmaceutically acceptable salt, solvate, or hydrate thereof,wherein: R³ and R^(3′) are each independently selected from the groupconsisting of —NR^(d)R^(e) and 4- to 9-membered monocyclic orspirocyclic non-aromatic heterocyclic rings, wherein the 4- to9-membered monocyclic or spirocyclic non-aromatic heterocyclic ringscontain from 1 to 3 N heteroatoms and are optionally substituted withfrom 1 to 2 substituents independently selected from the groupconsisting of oxo, —OH, and C₁₋₈ alkyl; R^(d) is selected from the groupconsisting of H and C₁₋₈ alkyl; R^(e) is selected from H, —C₁₋₈ alkyl,—X²—CONHSO₂—C₁₋₈ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₈ heterocyclyl, and—X²—C₄₋₈ heterocyclyl, wherein the alkyl or alkylene portions of R^(e)are optionally further substituted with from 1 to 2 substituentsindependently selected from OH, COOH, CONH₂, and COO—C₁₋₈ alkyl, and theC₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkyl portions of R^(e) are optionallysubstituted with 1 substituent independently selected from OH and oxo;X² is a C₁₋₆ alkylene and is optionally further substituted with OH; andR⁴ and R^(4′) are each independently selected from the group consistingof —O-ethyl, —O—CH₂-pyridyl optionally substituted with 1 —CN, and—O—CH₂-phenyl optionally substituted with 2 —CN.
 5. A compound ofFormula (II),

or a pharmaceutically acceptable salt, solvate, or hydrate thereof,wherein: Y′ is O or NH, each R^(2a) and R^(2a′) is independentlyselected from the group consisting of H, methyl, Cl, F, and —O-methyl;R³ and R^(3′) are each independently selected from the group consistingof —NR^(d)R^(e) and 4- to 9-membered monocyclic or spirocyclicnon-aromatic heterocyclic rings, wherein the 4- to 9-membered monocyclicor spirocyclic non-aromatic heterocyclic rings contain from 1 to 3 Nheteroatoms and are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of —OH and —OC(O)R^(g);R^(d) is selected from the group consisting of H and C₁₋₈ alkyl; R^(e)is selected from —C₁₋₈ alkyl and —C₁₋₆ alkylene-SO₃R^(g), wherein thealkyl or alkylene portions of R^(e) are optionally further substitutedwith from 1 to 2 substituents independently selected from OH, COOH, andCOO—C₁₋₈ alkyl; each R^(g) is independently selected from H and C₁₋₈alkyl optionally substituted with 1 to 2 NH₂; R⁴ and R^(4′) are eachindependently selected from the group consisting of H and −O-ethyl; m is0 or 1; and R^(6b′) is F.
 6. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, having the formula

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, having the formula

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim4, or a pharmaceutically acceptable salt thereof, wherein each R³ andR^(3′) is independently —NR^(d)R^(e).
 10. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein each R³ and R^(3′) isindependently selected from the group consisting of


11. The compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein each R³ and R^(3′) is independently a 4- to 9-memberedmonocyclic or spirocyclic non-aromatic heterocyclic ring containing from1 to 3 N heteroatoms and optionally substituted with from 1 to 2substituents independently selected from the group consisting of oxo,—OH, and C₁₋₈ alkyl.
 12. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein each R³ and R^(3′) is independently apiperidine, azetidine, pyrrolidine, 2λ²-azaspiro[3.3]heptane, or1λ²,3λ²,7λ²-triazaspiro[4.4]nonane ring which is optionally substitutedwith from 1 to 2 substituents independently selected from the groupconsisting of oxo, —OH, and C₁₋₈ alkyl.
 13. The compound of claim 4, ora pharmaceutically acceptable salt thereof, wherein each R³ and R^(3′)is independently an azetidine, 2λ²-azaspiro[3.3]heptane, or1λ²,3λ²,7λ²-triazaspiro[4.4]nonane ring which is optionally substitutedwith from 1 to 2 substituents independently selected from the groupconsisting of oxo, —OH, and C₁₋₈ alkyl.
 14. The compound of claim 4, ora pharmaceutically acceptable salt thereof, wherein each R³ and R^(3′)is independently selected from the group consisting of


15. The compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein the compound is an optically pure or enriched isomer.16. A pharmaceutical composition comprising a compound of claim 4, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 17. The compound of claim 5, or a pharmaceuticallyacceptable salt thereof, wherein Y′ is O.
 18. The compound of claim 5,or a pharmaceutically acceptable salt thereof, wherein each R³ andR^(3′) is independently —NR^(d)R^(e).
 19. The compound of claim 5, or apharmaceutically acceptable salt thereof, wherein each R³ and R^(3′) isindependently selected from the group consisting of


20. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein each R³ and R^(3′) is independently a 4- to 6-memberedmonocyclic or spirocyclic non-aromatic heterocyclic ring containing 1 Nheteroatom and optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of —OH and —OC(O)R^(g).21. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein each R³ and R^(3′) is independently a piperidine ringwhich is optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of —OH and —OC(O)R^(g).22. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein each R³ and R^(3′) is independently selected from thegroup consisting of


23. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein the compound is an optically pure or enriched isomer.24. A pharmaceutical composition comprising a compound of claim 5, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.